A single amino acid deletion in the ER Ca2+sensor STIM1 reverses the in vitro and in vivo effects of the Stormorken syndrome-causing R304W mutation

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60076658%3A12310%2F23%3A43906699" target="_blank" >RIV/60076658:12310/23:43906699 - isvavai.cz</a>

Result on the web

<a href="https://www.science.org/doi/10.1126/scisignal.add0509" target="_blank" >https://www.science.org/doi/10.1126/scisignal.add0509</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1126/scisignal.add0509" target="_blank" >10.1126/scisignal.add0509</a>

Result language

angličtina

Original language name

A single amino acid deletion in the ER Ca2+sensor STIM1 reverses the in vitro and in vivo effects of the Stormorken syndrome-causing R304W mutation

Original language description

Stormorken syndrome is a multiorgan hereditary disease caused by dysfunction of the endoplasmic reticulum (ER) Ca2+ sensor protein STIM1, which forms the Ca2+ release-activated Ca2+ (CRAC) channel together with the plasma membrane channel Orai1. ER Ca2+ store depletion activates STIM1 by releasing the intramolecular &quot;clamp&quot; formed between the coiled coil 1 (CC1) and CC3 domains of the protein, enabling the C terminus to extend and interact with Orai1. The most frequently occurring mutation in patients with Stormorken syndrome is R304W, which destabilizes and extends the STIM1 C terminus independently of ER Ca2+ store depletion, causing constitutive binding to Orai1 and CRAC channel activation. We found that in cis deletion of one amino acid residue, Glu296 (which we called E296del) reversed the pathological effects of R304W. Homozygous Stim1 E296del+R304W mice were viable and phenotypically indistinguishable from wild-type mice. NMR spec-troscopy, molecular dynamics simulations, and cellular experiments revealed that although the R304W muta-tion prevented CC1 from interacting with CC3, the additional deletion of Glu296 opposed this effect by enabling CC1-CC3 binding and restoring the CC domain interactions within STIM1 that are critical for proper CRAC channel function. Our results provide insight into the activation mechanism of STIM1 by clarifying the molecular basis of mutation-elicited protein dysfunction and pathophysiology.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10608 - Biochemistry and molecular biology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Science Signaling

ISSN

1945-0877

e-ISSN

1937-9145

Volume of the periodical

16

Issue of the periodical within the volume

771

Country of publishing house

US - UNITED STATES

Number of pages

17

Pages from-to

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UT code for WoS article

000937447600001

EID of the result in the Scopus database

2-s2.0-85147618029